SUMMARY / ABSTRACT Dr. Lockman has a long and successful track record mentoring more than 20 fellows, junior faculty, and students from the US and Africa in patient-oriented HIV research, seven of whom have secured K funding and four of whom are now R-funded . She is deeply committed to continuing and expanding this mentoring, which serves as the primary impetus for this K24 grant. Her mentees will have access to a wealth of research opportunities in the context of the many large HIV-focused clinical trials and studies that Dr. Lockman leads (and led over the past 18 years) in Botswana and elsewhere, ranging from randomized trials of antiretroviral or antibiotic regimens (many in pregnant women and their infants) to observational and epidemiologic studies of clinical outcomes among HIV-infected adults and HIV-exposed children. In the proposed K24, she will leverage the unique and extensive infrastructure, data and samples from a large ongoing randomized HIV combination prevention trial that she and others are conducting in 30 communities in Botswana (total population 180,000 with longitudinal cohort of 12,000 adults), in order to mentor investigators from Botswana and the US on pressing questions of substantial public health and clinical relevance to the severe epidemic still affecting sub-Saharan Africa. For context, UNAIDS is promoting high levels (90% or greater) of HIV diagnosis, antiretroviral treatment (ART) coverage, and virologic suppression (?90-90-90? targets) to end the HIV epidemic. However, despite nearly meeting these targets in Botswana, we observe annual HIV incidence >1%. Furthermore, with more than 15% of the adult population of Botswana on ART (and recent implementation of universal ART), it is essential that we understand the implications of widespread treatment for clinical outcomes and non-communicable disease incidence in persons living with HIV at the population level. We will therefore: a) Characterize adults with recent HIV infection using predictive analysis, in order to identify groups at highest risk for HIV acquisition in the current epidemic, and augment our understanding with individual in-depth interviews with recently- infected adults; b) Study the feasibility, acceptability, and uptake of a targeted approach to TDF/FTC pre- exposure prophylaxis, offered to HIV-negative persons meeting this high-risk profile; c) Evaluate the impact of HIV (and of early ART) on clinical outcomes, including c ancer incidence and hypertension prevalence in HIV-infected vs. HIV-uninfected adults, and HIV-related outcomes among persons starting dolutegravir- vs. efavirenz-based ART. In addition, Dr. Lockman will also mentor junior investigators on projects nested within a new large randomized IMPAACT trial of 3 antiretroviral regimens in pregnancy that that she leads, and in prior large perinatal HIV studies in Botswana that enrolled more than 9,000 mother-infant pairs. This K24 is critical, to support the protected time and resources that are required for Dr. Lockman to mentor junior investigators from both the US and Botswana in patient-oriented research.